Na2S2O4: A versatile reagent for the one-pot synthesis of 2-aryl-1h-imidazo[4,5-c]pyridines from 4-amino-3- nitropyridine and aldehydes via reductive cyclization

Article abstract of DOI:10.1080/00397910903011345

A highly efficient and versatile method for the synthesis of 2-aryl-1H-imidazo[4,5-c]pyridines 3 was achieved in one step via reductive cyclization of 4-amino-3-nitro-pyridines 4 with aromatic aldehydes in the presence of Na₂S₂O

Full text of DOI:10.1080/00397910903011345

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Na2S2O4: A Versatile Reagent for
the One-Pot Synthesis of 2-Aryl-1H-
imidazo[4,5-c]pyridines from 4-
Amino-3-nitropyridine and Aldehydes via
Reductive Cyclization
P. K. Dubey a , K. S. Chowdary a , B. Ramesh a & P. V. V. Prasada
Reddy a
a Department of Chemistry, College of Engineering, JNT University,
Kukatpally, Hyderabad, India
Version of record first published: 04 Feb 2010
To cite this article: P. K. Dubey, K. S. Chowdary, B. Ramesh & P. V. V. Prasada Reddy (2010): Na2S2O4:
A Versatile Reagent for the One-Pot Synthesis of 2-Aryl-1H-imidazo[4,5-c]pyridines from 4-Amino-3-
nitropyridine and Aldehydes via Reductive Cyclization, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 40:5, 697-708
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Synthetic Communications1, 40: 697–708, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903011345
Na2S2O4: A VERSATILE REAGENT FOR THE ONE-POT
SYNTHESIS OF 2-ARYL-1H-IMIDAZO[4,5-c]PYRIDINES
FROM 4-AMINO-3-NITROPYRIDINE AND ALDEHYDES
VIA REDUCTIVE CYCLIZATION
P. K. Dubey, K. S. Chowdary, B. Ramesh,
and P. V. V. Prasada Reddy
Department of Chemistry, College of Engineering, JNT University,
Kukatpally, Hyderabad, India
A highly efficient and versatile method for the synthesis of 2-aryl-1H-imidazo[4,5-c]pyri-
dines 3 was achieved in one step via reductive cyclization of 4-amino-3-nitro-pyridines 4
with aromatic aldehydes in the presence of Na2S2O4. Treatment of 3 with benzyl chloride
in nonaqueous media under phase-transfer conditions to afford N-benzylated derivatives 10.
Compounds 3 and 10 could also be prepared by other routes: dehydrogenative cyclization of
monoanil 4-amino-3-arylideneaminopyridine 11 with different oxidizing reagents resulted in
the formation of 3, and reduction of 11 with NaBH4, followed by cyclization with aromatic
acids using POCl3, gave the N-benzyl-2-aryl-imidazo[4,5-c]pyridines 10. Compound 11
could be synthesized from 3,4-diamino pyridine 1. The structures of all the compounds
obtained in the present work are supported by spectral and analytical data.
Keywords: 4-Amino-3-nitro-pyridine; aromatic aldehydes; benzyl chloride; Na2S2O4; one-pot; reductive
cyclization
INTRODUCTION
The benzimidazole[1–3] and imidazopyridine[4–6] moieties are important
pharmacophores that have proven to be useful for a number of biologically relevant
targets. 3,4-Diaminopyridine derivatives possess a wide range of biological activities[7]
such as treatment of multiple sclerosis[8] and antiviral, rodenticidal,[9] antimicrobial,
and cytotoxic[10] activities. 3,4-Diaminopyridine is a drug approved for clinical use in
the treatment of Lambert Eaton myasthenic syndrome.[11] Recently, it was
reported[12] that the 3,4-diamino pyridine derivative of 2-[(aryl)-methyl]sulfinyl-
1H-imidazo[4,5-c]pyridine was a potent antiosteoporotic agent, which was useful
in inhibiting bone resorption in a host animal, including humans. Medicinal chemists
consider these heterocycles to be privileged structures. Indeed, the development of
new synthetic methods, which could render accessible chemistry space currently not
attainable by existing methods, would be of considerable importance to chemistry.
Received February 8, 2009.
Address correspondence to B. Ramesh, Department of Chemistry, College of Engineering, JNT
University, Kukatpally, Hyderabad, AP 500 085, India. E-mail: rambetini@gmail.com
697

698
P. K. DUBEY ET AL.
Scheme 1. General route for synthesis for 2-substituted-1H-imidazo[4,5-c]pyridines.
The preparations of these compounds are usually straightforward, and a
number of synthetic methods are already available. The most popular synthetic
approaches for the synthesis of benzimidazoles and imidazopyridines generally
involve the condensation of diamines with carbonyl compounds[13–16] (Scheme 1).
For example, the reaction of 3,4-pyridinediamine (1) with carboxylic acid or acid
chloride results in intermediate amide (2). The latter, in turn, could undergo a cyclo-
dehydration reaction under strong acidic or harsh dehydrating conditions, often at
high temperatures, to afford imidazopyridines (3).
In continuation of our earlier work[17–20] on benzimidazoles and imidazo[4,5-
c]pyridines, we now report our studies on the synthesis of 1H-imidazo[4,5-c]pyri-
dines, in one pot via reductive cyclization using sodium dithionite without the need
for preparation or isolation of any intermediates, followed by aralkylation studies on
1H-imidazo[4,5-c]pyridines in nonaqueous media using triethylbenzylammonium
chloride (TEBAC) to get the selective products. We also report regioselective con-
densation of 3,4-diaminopyridines with aromatic aldehydes, followed by dehydro-
genative cyclization with different oxidizing reagents, to get the title compounds.
The results of our studies in this direction are presented in this communication.
RESULTS AND DISCUSSION
In an initial endeavor, a mixture of 4-amino-3-nitropyridine 4 with p-methoxy
benzaldehyde in ethanol in the presence of sodium dithionate (Na2S2O4) resulted in
the formation of 2-p-methoxy phenyl-1H-imidazo[4,5-c]pyridine 3a (i.e., 3, Ar ¼ -C6-
H4-4-OCH3), via reductive cyclization. This was confirmed on the basis of spectral
data and on an oxidation–reduction mechanism. An oxidation–reduction mech-
anism[21] (Scheme 2) is postulated here by condensation of an aldehyde with
4-amino-3-nitropyridine to form the corresponding imine 5. The subsequent
four-electron reduction of the nitro group, which results in hydroxylamine 6, fol-
lowed by cyclization to 2-aryl-1-N-hydroxy-imidazo[4,5-c]pyridine 7 and consequent
dehydration, could account for the formation of 2-aryl-1H-imidazo[4,5-c]pyridine 3.
This method leads to the exclusive formation of 2-aryl-1H-imidazo[4,5-c]pyridine in
good yield. It was proposed that entry to 2-aryl-1H-imidazo[4,5-c]pyridine might
involve the intermediacy of primary amine, the six-electron reduction product of
nitroimine, and subsequently the oxidation of imidazoline.
An authentic sample was also obtained by direct condensation of 3,4-diamino-
pyridine 1 with p-methoxy benzoic acid in refluxing POCl3 conditions using the
literature procedure.[22,23]
To extend the scope of the reaction and to generalize the procedure, a variety
of electronically divergent aromatic aldehydes and 4-amino-3-nitropyridine 4 were

IMIDAZOPYRIDINES BY REDUCTIVE CYCLIZATION
699
Scheme 2. The possible reaction mechanism.
examined, and the results are summarized in the experimental section. In all cases,
aromatic aldehydes carrying either an electron-withdrawing group or electron-
donating group reacted successfully and gave the products in good yields. The results
proved that this method is superior to the previously reported method in terms of
good yields, one-pot cyclization, few steps, and simple processing.
Puerstinger and coworkers reported[24] that the benzylations on 2-aryl-1H-
imidazo[4,5-c]pyridine 3 with substituted benzyl halides in dimethylformanide
(DMF) solvent using 50% NaOH solution as a base gave an N-benzylated derivative
on pyridine in imidazopyridines, not on an imidazole ring. We carried out the ben-
zylation reactions under phase-transfer catalytic (PTC) conditions, using K2CO3 as a
mild base and a catalytic amount of KI, regardless of whether N-benzylation occurs
on the imidazole ring or pyridine ring.
Reaction of 3a (Ar ¼ -C6H4-4-OCH3) with benzyl chloride in CH3CN using
TEBAC as a PTC, anhyd. K2CO3 as base, and a catalytic amount of KI under
anhydrous conditions at room temperature (2 h) afforded the 1-benyl-2-p-
methoxyphenyl-1H-imidazo[4,5-c]pyridine 10a (Ar ¼ -C6H4-4-OCH3, Ar0 ¼ -C6H5)
selectively. It was confirmed on the basis of spectral data (Scheme 3). When the same
reaction was carried out in the absence of KI, the reaction completed in 10–12 h.
Perchance, conversion of 3a to corresponding 10a is favored in the presence of
KI. This is probably because in presence of KI, chlorine of benzyl is initially replaced
by iodine, and subsequent reaction of iodo derivative of benzyl with the nitrogen
nucleophile such as 1H-imidazo[4,5-c]pyridine 3 is facile.
Scheme 3. Preparation of 2-aryl-1H-imidazo[4,5-c]pyridines followed by aralkylation.

700
P. K. DUBEY ET AL.
Scheme 4. Preparation of 2-aryl-1H-imidazo[4,5-c]pyridines using oxidative dehydrogenating agents.
The reaction between 4 and 4-methoxy benzaldehyde, followed by benzylation
studies, has been found to be general, and it has been extended to other aromatic
aldehydes, followed by reactions with benzyl chloride in nonaqueous medium. The
products thus obtained were assigned structures 3 and 10, respectively, on the basis
of spectral and analytical data (Scheme 3).
Alternatively, the compounds 3 and 10 can also be synthesized another two
sequences of reactions as shown in Schemes 4 and 5.
Alternatively, compound 3 could also be synthesized by the following sequence
of reactions. Reduction of 4 with H2=Pd-C in ethanol gave previously reported[25–27]
3,4-diaminopyridine 1. The condensation of 1 with p-methoxy benzaldehyde in
ethanol under refluxing conditions,[20] followed by simple processing, yielded pro-
duct 11a (Ar ¼ -C6H4-4-OCH3), which was found to be homogeneous on thin-layer
1
chromatography (TLC). Its infrared (IR), H NMR, and mass spectral data indi-
cated it to be a monoanil formed by a simple 1:1 condensation of 1 with p-methoxy
benzaldehyde. The latter, on dehydrogenative cyclization using oxidizing agents such
as lead tetraacetate [Pb(OAc)4] in acetic acid, followed by simple aqueous workup,
once again gave 3a in good yield (Scheme 4). This was confirmed based on compari-
son of thin-layer chromatography (TLC) results mp, mmp, and super-impossible IR
with those of the compounds obtained through the one-pot reductive cyclization
approach (Scheme 3).
Further, we examined with other oxidative dehydrogenating agents, such as
cupric acetate [Cu(OAc)2] and nitrobenzene (Ph-NO2), for the dehydrogenative
cyclization of 11a to get 3a. The reaction of 11 with cupric acetate [Cu(OAc)2] in
acetic acid, followed by simple processing, resulted in the formation of respective
2-p-methoxyphenyl-1H-imidazo[4,5-c]pyridine 3a (i.e., 3, Ar ¼ -C6H4-4-OCH3), in
good yields. Similarly, when nitrobenzene was used as an oxidizing reagent, it gave
the same results. See experimental data for yields (Scheme 4).
Compound 10 could also be synthesized another sequence of reactions as
shown [i.e., reduction of Schiff’s base 11a with NaBH4 in ethanol at room tempera-
ture, resulting in the formation of 3-benzylamino-4-aminopyridine 12a, which on
cyclization with p-methoxy benzoic acid in refluxing POCl3 gave 10a (Ar ¼ -C6H4-
4-OCH3, Ar0 ¼ -C6H5)]. This product is identical with compound obtained from 3a
Scheme 5. Preparation of N-aralkyl-1H-imidazo[4,5-c]pyridines.

IMIDAZOPYRIDINES BY REDUCTIVE CYCLIZATION
701
using benzyl chloride under nonaqueous conditions in the presence of K2CO3 in all
1
respects (mp, TLC, H NMR, mass).
Based on these results, when benzylation reactions are carried out using K2CO3
as a base in nonaqueous medium in the presence of a PTC such as TEBAC, the
benzylation occurs on the imidazole ring, not on the pyridine ring as in
imidazopyridines.
CONCLUSION
In summary, we have found an efficient and versatile method for the prep-
aration of a series of 2-aryl-1H-imidazo[4,5-c]pyridines in one pot via reductive cycli-
zation from 4-amino-3-nitropyridines and various aromatic aldehydes using solid
Na2S2O4, followed by benzylation studies on imidazopyridines under PTC con-
ditions using TEBAC. In this article, we also reprot alternate synthesis of 2-
aryl-1H-imidazo[4,5-c]pyridines and 1-benyl-2-aryl-1H-imidazo[4,5-c] pyridines.
EXPERIMENTAL
General Conditions
Melting points were determined in open glass capillaries using a Buchi
melting-point apparatus and are uncorrected. IR spectra were recorded on sample
as diluted solutions (chloroform or carbon tetrachloride) in matched sodium
chloride cells or as potassium bromide pellets with a Perkin IR spectrometer. All
1H NMR spectra were recorded on a Varian 200-MHz instrument with an internal
standard of tetramethylsilane. Mass spectra were recorded on an Agilent-LC-MS
instrument giving only Mþ values using (M.þ þ 1) mode. Analytical TLC was per-
.
formed with silica gel GF254 from Merck (Germany) containing a fluorescent indi-
cator. Spots were detected with ultraviolet (UV) light or iodine. Column
chromatography was performed with Baker 60 to 120-mesh silica gel. The starting
materials 1 and 4 were prepared from 4-amino pyridine using a known procedure.[28]
The following experimental procedures are representive of the general procedures
used to synthesize all compounds.
Preparation of 3 Using Na2SO4
A mixture of 4 (1.39 g, 10 mmol) and aromatic aldehyde (10 mmol) in EtOH
(20 mL) was treated with solid Na2S2O4 (1.75 g, 10 mmol), then heated at 80ꢀC for
4 h. The progress of reaction was monitored on TLC for the disappearance of 4.
At the end of this period, the mixture was poured into 5 N aqueous NH4OH sol-
ution; the precipitated solid was filtered, washed with water, dried, and recrystallized
from suitable solvent to obtain pure 3 (Scheme 3).
Data
2-(4-Methoxy-phenyl)-imidazo[4,5-c]pyridine (3a). Ar ¼ -C6H4-4-OCH3,
1
yield 88%, mp 268–70ꢀC; IR (KBr): 3415 cmꢁ1 (b, -NH); H NMR (CDCl3=TMS)

702
P. K. DUBEY ET AL.
d 3.8 (s, 3H, -OCH3), 7.2–7.4 (m, 2H, Ar-H), 7.4–7.6 (m, 1H, Ar-H), 8.0–8.2 (m, 2H,
Ar-H), 8.2–8.4 (m, 1H, Ar-H), 8.9 (s, 1H, Ar-H), 13.0 (s, 1H, -NH); M.þ þ 1: 226.
Anal. calcd. for (C13H11N3O): C, 69.32; H, 4.92; N, 18.66. Found: C, 69.26; H,
4.86; N, 18.58%.
2-p-Tolyl-imidazo[4,5-c]pyridine (3b). Ar ¼ -C6H4-4-CH3, yield 90%, mp
1
268–270ꢀC; IR (KBr): 3434 cmꢁ1 (b, -NH); H NMR (CDCl3=TMS) d 2.4 (s, 3H,
-CH3), 7.2–7.4 (m, 3H, Ar-H), 7.8–8.0 (m, 2H, Ar-H), 8.0–8.2 (m, 1H, Ar-H),
8.95 (s, 1H, Ar-H), 13.1 (s, 1H, -NH); M.þ þ 1: 210. Anal. calcd. for (C13H11N3):
C, 74.62; H, 5.30; N, 20.08, Found: C, 74.56; H, 5.24; N, 20.00%.
2-Phenyl-imidazo[4,5-c]pyridine (3c). Ar ¼ -C6H5, yield 84%, mp 230–232ꢀC;
1
IR (KBr): 3441 cmꢁ1 (b, -NH); H NMR (CDCl3=TMS) d 7.3–7.6 (m, 4H, Ar-H),
8.1–8.3 (m, 3H, Ar-H), 8.90 (s, 1H, Ar-H), 12.95 (s, 1H, -NH); M.þ þ 1: 196. Anal.
calcd. for (C12H9N3): C, 73.83; H, 4.65; N, 21.52, Found: C, 73.76; H, 4.61; N,
21.48%.
2(4-Chloro-phenyl)-imidazo[4,5-c]ꢁp1yridine (3d). Ar ¼ -C6H4-4-Cl, yield
1
84%, mp 246–248ꢀC; IR (KBr): 3436 cm (b, -NH2); H NMR (CDCl3=TMS):
d 7.4–7.6 (m, 4H, Ar-H), 8.2–8.4 (m, 2H, Ar-H), 8.90 (s, 1H, Ar-H), 13.0 (s, 1H,
-NH); M.þ þ 1: 230. Anal. calcd. for (C12H8ClN3): C, 62.76; H, 3.51; N, 18.30,
Found: C, 62.70; H, 3.46; N, 18.26%.
2(2-Chloro-phenyl)-imidazo[4,5-c]pyridine (3e). Ar ¼ -C6H4-2-Cl, yield
82%, mp 296–298ꢀC; IR (KBr): 3432 cmꢁ1 (b, -NH2); 1H NMR (CDCl3=TMS)
d 7.2–7.4 (m, 4H, Ar-H), 8.0–8.2 (m, 2H, Ar-H), 8.90 (s, 1H, Ar-H), 12.9 (s, 1H,
-NH); M.þ þ 1: 230. Anal. calcd. for (C12H8ClN3): C, 62.76; H, 3.51; N, 18.30,
Found: C, 62.72; H, 3.42; N, 18.24%.
2(4-Nitro-phenyl)-3H-imidazo[4,5-c]pyridine (3f). Ar ¼ -C6H4-4-NO2, yield
1
82%, mp > 300ꢀC; IR (KBr): 1514 (-NO2), 3452–3449 cmꢁ1 (b, -NH); H NMR
(CDCl3=TMS) d 7.2–7.4 (m, 3H, Ar-H), 7.8–8.0 (m, 2H, Ar-H), 8.0–8.2 (m, 1H,
Ar-H), 8.95 (s, 1H, Ar-H), 12.95 (s, 1H, -NH); M.þ þ 1: 241. Anal. calcd. for
(C12H8N4O2): C, 60.00; H, 3.36; N, 23.32. Found: C, 59.96; H, 3.30; N, 23.26%.
2-o-tolyl-3H-imidazo[4,5-c]pyridine (3g). Ar ¼ -C6H4-2-CH3, yield 84%,
1
mp 260–262ꢀC; IR (KBr): 3435 cmꢁ1 (b, -NH); H NMR (CDCl3=TMS) d 2.35
(s, 3H, -CH3), 7.0–7.2 (m, 3H, Ar-H), 7.8–8.0 (m, 2H, Ar-H), 8.0–8.2 (m, 1H,
Ar-H), 8.90 (s, 1H, Ar-H), 13.0 (s, 1H, -NH); M.þ þ 1: 210. Anal. calcd. for
(C13H11N3): C, 74.62; H, 5.30; N, 20.08. Found: C, 74.52; H, 5.25; N, 20.00%.
[4-(3H-Imidazo[4, 5-c]pyridine-2-yl]-dimethyl Amine (3h). Ar ¼ -C6H4-
4-NMe2, yield 80%, mp 292–294ꢀC; IR (KBr): 3440 cmꢁ1 (b, -NH); 1H NMR
(CDCl3=TMS) d 2.85 (s, 6H, -NMe2) 6.8–7.0 (m, 2H, Ar-H), 7.4–7.8 (m, 3H,
Ar-H), 8.0–8.1 (m, 1H, Ar-H); 8.95 (s, 1H, Ar-H), 12.95 (s, 1H, -NH); M.þ þ 1:
239. Anal. calcd. for (C14H14N4): C, 70.57; H, 5.92; N, 23.51. Found: C, 70.51; H,
5.84; N, 23.43%.

IMIDAZOPYRIDINES BY REDUCTIVE CYCLIZATION
703
Preparation of 10 (Benzylation of 3)
K2CO3 (1.52 g, 11 mmol) and KI (0.16 g, 1 mmol) were added to a solution of
TEBAC (0.2 g) in CH3CN (10 mL), and the mixture was stirred at RT for 10 min. To
this mixture, under stirring, a solution of 3 (10 mmol) in CH3CN (5 mL) was added,
which was then stirred another 10 min. Benzyl chloride (11 mmol) was added. The
whole reaction mass was stirred at rT. The progress of the reaction was monitored
by TLC for the disappearance of 3. On completion of the reaction (ꢂ2 h), the mix-
ture was diluted with water. The solid product was thrown out from the reaction
mass, filtered, washed with water, and dried to give crude 10. The crude product
was recrystallized from suitable solvent and gave 10 in moderate yields (Scheme 3).
Data
3-Benzyl-2-(4-methoxy-phenyl)-imidazo[4,5-c]pyridine (10a). Ar ¼ -C6-
1
H4-4-OCH3, yield 86%, mp 226–228ꢀC; H NMR (CDCl3=TMS) d 3.84 (s, 3H,
-OCH3), 5.40 (s, 2H, -CH2-), 7.20–7.35(m, 7H, Ar-H), 7.3–7.7 (m, 2H, Ar-H),
8.25–8.35 (m, 2H, Ar-H), 8.52 (s, 1H, Ar-H); M.þ þ 1: 316. Anal. calcd. for
(C20H17N3O): C, 76.17; H, 5.43; N, 13.32. Found: C, 76.12; H, 5.36; N, 13.26%.
3-Benzyl-2-p-tolyl-imidazo[4,5-c]pyridine (10b). Ar ¼ -C6H4-4-CH3, yield
1
88%, mp 230–232ꢀC; H NMR (CDCl3=TMS) d 2.41 (s, 3H, -CH3), 5.41 (s, 2H,
-CH2-), 7.21–7.31 (m, 7H, Ar-H), 7.4–7.7 (m, 2H, Ar-H), 8.2–8.3 (m, 2H, Ar-H),
8.4 (s, 1H, Ar-H); M.þ þ 1: 300. Anal. calcd. for (C20H17N3): C, 80.24; H, 5.72;
N, 14.07. Found: C, 80.18; H, 5.66; N, 13.98%.
3-Benzyl-2-phenyl-imidazo[4,5-c]pyridine (10c). Ar ¼ -C6H5, yield 78%,
1
mp 216–218ꢀC; H NMR (CDCl3=TMS) d 5.38 (s, 2H, -CH2-), 7.25–7.40 (m, 8H,
Ar-H), 7.6–7.7(m, 2H, Ar-H), 8.1–8.2 (m, 2H, Ar-H), 8.45 (s, 1H, Ar-H); M.þ þ 1:
286. Anal. calcd. for (C19H15N3): C, 79.98; H, 5.30; N, 14.73. Found: C, 79.92; H,
5.26; N, 14.68%.
3-Benzyl-2-(4-chloro-phenyl)-imidazo[4,5-c]pyridine (10d). Ar ¼ -C6H4-
1
4-Cl, yield 72%, mp 246–248ꢀC; H NMR (CDCl3=TMS): d 5.40 (s, 2H, -CH2-),
7.0–7.4 (m, 7H, Ar-H), 7.4–7.6 (m, 2H, Ar-H), 7.9–8.0 (s, 2H, Ar-H), 8.48 (s, 1H,
Ar-H); M.þ þ 1: 320. Anal. calcd. for (C19H14ClN3): C, 71.36; H, 4.41; N, 13.14.
Found: C, 71.32; H, 4.35; N, 13.06%.
Preparation of 11 (General Procedure)
A mixture of 1 (1.09 g, 10 mmol) and respective aldehydes (10 mmol) in ethanol
(20 mL) was stirred at reflux until the condensation was complete as shown by TLC.
At the end of this period, ethanol was removed under reduced pressure. The residual
crude 11, thus obtained, was purified by column chromatography using hexane and
ethyl acetate (9:1) to give 11 as a pure product.

704
P. K. DUBEY ET AL.
Data
(E)-N3-(4-Methoxybenzylidene)pyridine-3,4-diamine (11a). Ar ¼ -C6H4-
4-OCH3, yield ¼ 95%, mp 48–50ꢀC; IR (KBr) 3435–3433 cmꢁ1 (b, doublet, -NH2);
1H NMR (DMSO-d6=TMS) showed signals at d 3.8 (s, 3H, -OCH3), 4.6 (bs, 2H,
-NH2), 6.6–6.8 (d, J ¼ 5.4 Hz, 1H, pyridine proton 5th), 7.4–8.3 (m, 6H, four phenyl
and two pyridyl), 8.3 (s, 1H ¼ CH, vinyl proton); M.þ þ 1: 228. Anal. calcd. for
(C13H13N3O): C, 68.70; H, 5.77; N, 18.49. Found: C, 68.64; H, 5.72; N, 18.44%.
(E) N3-(4-Methylbenzylidene)pyridine-3,4-diamine (11b). Ar ¼ -C6H4-
4-CH3, yield 92%, mp 40–42ꢀC; IR (KBr) 3427–3431 cmꢁ1 (b, doublet, -NH2);
1H NMR (DMSO-d6=TMS) showed signals at d 2.4 (s, 3H, -CH3), 4.65 (bs, 2H,
-NH2), 6.55–6.75 (d, J ¼ 5.4 Hz, 1H, pyridine proton 5th), 7.4–8.2 (m, 6H, four
phenyl and two pyridyl), 8.25 (s, 1H ¼ CH, vinyl proton); M.þ þ 1: 212. Anal. calcd.
for (C13H13N3): C, 73.91; H, 6.20; N, 19.89. Found: C, 73.86; H, 6.12; N, 19.85%.
(E)-N3-Benzylidenepyridine-3,4-diamine (11c). Ar ¼ -C6H5, yield 90%,
1
mp 29–31ꢀC; IR (KBr) 3452–3449 cmꢁ1 (b, doublet, -NH2); H NMR (DMSO-d6=
TMS) showed signals at d 5.0 (bs, 2H, -NH2), 6.6–6.8 (d, J ¼ 5.2 Hz, 1H, pyridine
proton 5th), 7.4–8.2 (m, 7H, five phenyl and two pyridyl) & 8.4 (s, 1H ¼ CH, vinyl
proton); M.þ þ 1: 198. Anal. calcd. for (C12H11N3): C, 73.07; H, 5.62; N, 21.30.
Found: C, 72.97; H, 5.58; N, 21.22%.
(E)-N3-(4-Chlorobenzylidene)pyridine-3,4-diamine (11d). Ar ¼ -C6H4-4-Cl,
1
yield 95%, mp 38–40ꢀC; IR (KBr) 3429–3428 cmꢁ1(b, doublet, -NH2); H NMR
(DMSO-d6=TMS) showed signals at d 4.6 (bs, 2H, -NH2), 6.55 (d, J ¼ 5.0 Hz, 1H,
pyridine 5th), 7.45–8.1 (m, 6H, four phenyl and two pyridyl), 8.2 (s, 1H ¼ CH, vinyl
proton); M.þ þ 1: 232. Anal. calcd. for (C12H10ClN3): C, 62.21; H, 4.35; N, 18.14.
Found: C, 62.16; H, 4.31; N, 18.06%.
(E)-N3-(2-Chlorobenzylidene)pyridine-3,4-diamine (11e). Ar ¼ -C6H4-2-Cl,
1
yield ¼ 88%, mp 45–47ꢀC; IR (KBr) 3454–3451 cmꢁ1 (b, doublet, -NH2); H NMR
(DMSO-d6=TMS) showed signals at d 4.68 (bs, 2H, -NH2), 6.6 (d, J ¼ 5.2 Hz, 1H,
pyridine 5th), 7.4–8.3 (m, 6H, four phenyl and two pyridyl), 9.55 (s, IH ¼ CH, vinyl
proton); M.þ þ 1: 232. Anal. calcd. for (C12H10ClN3): C, 62.21; H, 4.35; N, 18.14.
Found: C, 62.16; H, 4.28; N, 18.08%.
(E)-N3-(4-Nitrobenzylidene)pyridine-3,4-diamine (11f). Ar ¼ -C6H4-4-NO2,
1
yield 95%, mp 53–55ꢀC; IR (KBr): 3409–3454 cmꢁ1 (b, doublet, -NH2); H NMR
(DMSO-d6=TMS) showed signals at d 5.5 (bs, 2H, -NH2), 6.55 (d, J ¼ 5.3 Hz, 1H,
pyridine 5th), 7.45–8.1 (m, 6H, four phenyl and two pyridyl), 8.2 (s, 1H ¼ CH, vinyl
proton); M.þ þ 1: 243. Anal. calcd. for (C10H10N4O2): C, 59.50; H, 4.16; N, 23.13.
Found: C, 59.44; H, 4.10; N, 23.06%.
Cyclization of 11 Under Different Conditions
With nitro benzene. A mixture of 11 (10 mmol) and nitro benzene (20 mL)
was heated under reflux (210–215ꢀC) for 2 h. The progress of the reaction was mon-
itored on TLC for the disappearance of 11. After completion of reaction, the solvent
was removed under reduced pressure to get residue 2. The residue was triturate with

IMIDAZOPYRIDINES BY REDUCTIVE CYCLIZATION
705
hexane to get free-flowing solid. It was purified by column chromatography using
hexane and ethyl acetate (8:2) to yield a pure 3 in good yields (Scheme 4).
Yields (%): 3a ¼ 84, 3b ¼ 82, 3c ¼ 80, 3d ¼ 82, 3e ¼ 78, and 3f ¼ 78.
With Pb(OAc)4 (or) Cu(OAc)2. The respective dehydrogenating agent [(i.e.,
Pb(OAc)4 (or) Cu(OAc)2(10 mmol)] to a solution of 11 (10 mmol) in acetic acid
(20 mL) was added at room temperature, and the mixture was stirred for 1 h at
80ꢀC. At the end of this period, the reaction mixture was cooled to room tempera-
ture and poured into ice-cold water (100 mL). The separated solid was filtered,
washed with water (2 ꢃ 50 mL) and dried. The crude products were recrystallized
from suitable solvent to get pure 3.
Yield (%): (Pb(OAc)4=Cu(OAc)2): 3a ¼ 79=86, 3b ¼ 80=84, 3c ¼ 79=80,
3d ¼ 74=78, 3e ¼ 78=82, and 3f ¼ 78=76.
Typical Procedure for Reduction of 11 (Schiff’s Base)
Sodium borohydride (0.38 g, 10 mmol) was added to a solution of 11 (10 mmol)
in methanol (30 mL) portionwise at 20–25ꢀC with stirring. After completion of the
addition (10–15 min), the reaction mixture was heated on a water bath for 1 h until
the reaction went to completion as shown by TLC. Then the reaction mixture was
cooled to room temperature and treated with water. The separated solid was filtered,
washed with water (2 ꢃ 40 mL), and dried to obtain a crude product, which on
recrystallization from ethanol gave pure 12.
Data
N3-(4-Methoxybenzyl)pyridine-3,4-diamine (12a). Ar ¼ -C6H4-4-OCH3, yield
69%, mp 132–134ꢀC; IR (KBr): 3408 cmꢁ1 (-NH); 1H NMR (DMSO-d6=TMS) d 2.3
(bs, 2H, -NH2), 3.8 (s, 3H, -OCH3), 3.9 (bs, 1H, -NH2), 4.2 (s, 2H, -CH2-), 6.6 (d,
J ¼ 5.2 Hz, 1H, pyridine 5th), 6.9–7.3 (m, 4H, phenyl), 7.8 (d, J ¼ 6.2 Hz, 2H, pyri-
dine); M.þ þ 1: 230. Anal. calcd. for (C13H15N3O): C, 68.10. H, 6.59; N, 18.33.
Found: C, 68.02; H, 4.06; N, 23.00%.
N3-(4-Methylbenzyl)-pyridine-3,4-diamine (12b). Ar ¼ -C6H4-4-CH3, yield
1
72%, mp 152–54ꢀC; IR (KBr): 3428 cmꢁ1 (-NH); H NMR (DMSO-d6=TMS) d
2.4 (s, 3H, -CH3), 3.35 (bs, 1H, -NH), 4.2 (bs, 2H, -NH2), 4.4 (s, 2H, -CH2-), 6.55
(d, J ¼ 5.4 Hz, 1H, Pyridine 5th), 7.4–8.2 (m, 7H, phenyl and two pyridyl);
M.þ þ 1: 214. Anal. calcd. for (C13H15N3): C, 73.21; H, 7.09; N, 19.70. Found: C,
73.15; H, 7.02; N, 19.62%.
N3-Benzylpyridine-3,4-diamine (12c). Ar ¼ -C6H5, yield 70%, mp 169–71ꢀC;
1
IR (KBr): 3437 cmꢁ1 (-NH); H NMR (DMSO-d6=TMS) d 3.4 (bs, 1H, -NH), 4.0
(bs, 2H, -NH2), 4.6 (s, 2H, -CH2-), 6.5 (d, J ¼ 5.2 Hz, 1H, pyridine 5th), 7.5–8.3
(m, 7H, phenyl and two pyridyl); M.þ þ 1: 200. Anal. calcd. for (C12H13N3): C,
72.33; H, 6.58; N, 21.09. Found: C, 72.26; H, 4.06; N, 21.01%.
N3-(4-Chlorobenzyl)pyridine-3,4-diamine (12d). Ar ¼ -C6H4-4-Cl, yield 72%,
1
mp 146–148ꢀC; IR (KBr): 3416 cmꢁ1 (-NH); H NMR (DMSO-d6=TMS) d 3.3 (bs,
1H, -NH-), 4.0 (bs, 2H, -NH2), 4.3 (s, 2H, -CH2-), 6.5 (d, J ¼ 5.4 Hz, 1H, pyridine

706
P. K. DUBEY ET AL.
5th), 7.3–7.4 (m, 4H, phenyl), 7.8 (d, J ¼ 6.2 Hz, 2H, pyridine); M.þ þ 1: 234. Anal.
calcd. for (C12H12ClN3): C, 61.67; H, 5.18; N, 17.98. Found: C, 61.64; H, 5.14; N,
17.92%.
N3-(2-Chlorobenzyl)pyridine-3,4-diamine (12e). Ar ¼ -C6H4-2-Cl, yield 71%,
1
mp 136–138ꢀC; IR (KBr): 3408 cmꢁ1 (-NH); H NMR (DMSO-d6=TMS) d 3.4 (bs,
1H, -NH-), 4.3 (bs, 2H, -NH2), 4.6 (s, 2H, -CH2-), 6.7 (d, J ¼ 5.6 Hz, 1H, pyridine
5th), 7.5–7.8 (m, 4H, phenyl), 7.8 (d, J ¼ 6.2 Hz, 2H, pyridine); M.þ þ 1: 234. Anal.
calcd. for (C12H12ClN3): C, 61.67; H, 5.18; N, 17.98. Found: C, 61.65; H, 5.15; N,
17.94%.
N3-(4-Nitrobenzyl)pyridine-3,4-diamine (12f). Ar ¼ -C6H4-4-NO2, yield 81%,
1
mp 191–193ꢀC; IR (KBr): 1514 (-NO2), 3410 cmꢁ1 (-NH); H NMR (DMSO-d6=
TMS) d 3.4 (bs, 1H, -NH-), 4.0 (bs, 2H, -NH2), 4.7 (s, 2H, -CH2-), 6.6 (d, J ¼ 5.2 Hz,
Hz, 1H, pyridine 5th), 7.5–8.6 (m, 4H, phenyl protons), 7.8 (d, J ¼ 7.2 Hz, 2H, pyri-
dine protons); M.þ þ 1: 245. Anal. calcd. for (C12H12N4O2): C, 59.01; H, 4.95; N,
22.94. Found: C, 58.95; H, 4.89; N, 22.90%.
Preparation of 10 from 12
A mixture of 12 (10 mmol) and aromatic acid (10 mmol) was added to POCl3
(20 mL), and the resulting mixture was heated to reflux for 4 h. The progress of the
reaction was monitored by TLC. On completion of reaction, excess of POCl3 was
removed under reduced pressure. The residue was treated with ice-cold water and
neutralized with aqueous NaOH solution. The precipitated product was filtered,
washed with water, and dried to give crude 10. The crude products were recrystal-
lized from a suitable solvent to get pure 10 in good yields.
Yields (%): 10a ¼ 73, 10b ¼ 69, 10c ¼ 68, and 10d ¼ 71.
ACKNOWLEDGMENTS
We thank Azakem Laboratories Pvt. Ltd. management for encouragement and
the staff of the analytical laboratories of our research center for spectral analyses.
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